Abstract
Resuscitation with pure oxygen at birth after fetal asphyxia may aggravate brain damage by inducing pro-inflammation. The toll-like receptors (TLRs) may serve a pro-inflammatory role in hyperoxemia during ischemia-reperfusion. Sixteen near-term fetal sheep (132-136 d) were subjected to 10 min of cord occlusion, delivery and mechanical ventilation with 100% O2 (n = 8), or 21% O2 (n = 8) for 30 min followed by normoxemia for 90 min. Eight sheep fetuses were delivered immediately with inspired O2 targeted at normoxemia for 120 min (controls). Levels and distributions of mRNAs for IL-1β, TNF-α, IL-12p40, IL-18, IL-6, IL-10, IFN-γ, TLR-2, -3 and -4 in cerebral tissue at 2 h after birth were evaluated with real-time polymerase chain reaction (PCR) and in situ hybridization. Expressions of IL-1β, IL-12p40, TLR-2, and TLR-4 were increased in cortex/subcortex after resuscitation with 100% O2 compared with 21% O2 (all p < 0.05) and to controls (all p < 0.05). Increased cellular expression of IL-1β was localized to sub-meningeal cortical layers and to sub-cortical white matter. Hyperoxic resuscitation at birth following fetal asphyxia induces a cerebral pro-inflammatory response with an up-regulation of TLR-2 and -4. These may be early events leading to increased tissue damage after exposure to hyperoxemia at birth.
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Abbreviations
- MABP:
-
mean arterial blood pressure
- TLR:
-
toll-like receptor
References
Graulich J, Hoffmann U, Maier RF, Ruscher K, Pomper JK, Ko HK, Gabriel S, Obladen M, Heinemann U 2002 Acute neuronal injury after hypoxia is influenced by the reoxygenation mode in juvenile hippocampal slice cultures. Brain Res Dev Brain Res 137: 35–42
Munkeby BH, Borke WB, Bjornland K, Sikkeland LI, Borge GI, Halvorsen B, Saugstad OD 2004 Resuscitation with 100% O2 increases cerebral injury in hypoxemic piglets. Pediatr Res 56: 783–790
Saugstad OD, Ramji S, Vento M 2005 Resuscitation of depressed newborn infants with ambient air or pure oxygen: a meta-analysis. Biol Neonate 87: 27–34
Vento M, Asensi M, Sastre J, Lloret A, Garcia-Sala F, Vina J 2003 Oxidative stress in asphyxiated term infants resuscitated with 100% oxygen. J Pediatr 142: 240–246
Vento M, Sastre J, Asensi MA, Vina J 2005 Room-air resuscitation causes less damage to heart and kidney than 100% oxygen. Am J Respir Crit Care Med 172: 1393–1398
Felderhoff-Mueser U, Bittigau P, Sifringer M, Jarosz B, Korobowicz E, Mahler L, Piening T, Moysich A, Grune T, Thor F, Heumann R, Buhrer C, Ikonomidou C 2004 Oxygen causes cell death in the developing brain. Neurobiol Dis 17: 273–282
Felderhoff-Mueser U, Sifringer M, Polley O, Dzietko M, Leineweber B, Mahler L, Baier M, Bittigau P, Obladen M, Ikonomidou C, Buhrer C 2005 Caspase-1-processed interleukins in hyperoxia-induced cell death in the developing brain. Ann Neurol 57: 50–59
Kopp E, Medzhitov R 2003 Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol 15: 396–401
Li M, Carpio DF, Zheng Y, Bruzzo P, Singh V, Ouaaz F, Medzhitov RM, Beg AA 2001 An essential role of the NF-kappa B/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. J Immunol 166: 7128–7135
Thorngren-Jerneck K, Ley D, Hellstrom-Westas L, Hernandez-Andrade E, Lingman G, Ohlsson T, Oskarsson G, Pesonen E, Sandell A, Strand SE, Werner O, Marsal K 2001 Reduced postnatal cerebral glucose metabolism measured by PET after asphyxia in near term fetal lambs. J Neurosci Res 66: 844–850
Bradley DJ, Towle HC, Young WS 3rd 1992 Spatial and temporal expression of alpha- and beta-thyroid hormone receptor mRNAs, including the beta 2-subtype, in the developing mammalian nervous system. J Neurosci 12: 2288–2302
Ley D, Oskarsson G, Bellander M, Hernandez-Andrade E, Lingman G, Marsal K, Olsson T, Pesonen E, Thorngren-Jerneck K, Werner O, Hellstrom-Westas L 2004 Different responses of myocardial and cerebral blood flow to cord occlusion in exteriorized fetal sheep. Pediatr Res 55: 568–575
Hagberg H, Gilland E, Bona E, Hanson LA, Hahin-Zoric M, Blennow M, Holst M, McRae A, Soder O 1996 Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats. Pediatr Res 40: 603–609
Cai Z, Pang Y, Lin S, Rhodes P 2003 Differential roles of tumor necrosis factor-a and interleukin-1b in lipopolysaccharide-induced brain injury in the neonatal rat. Brain Res 975: 37–47
Loddick SA, Rothwell NJ 1996 Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab 16: 932–940
Quan N, Stern EL, Whiteside MB, Herkenham M 1999 Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat. J Neuroimmunol 93: 72–80
Trinchieri G 1998 Immunobiology of interleukin-12. Immunol Res 17: 269–278
Yamada M, Kubo H, Kobayashi S, Ishizawa K, Sasaki H 2004 Interferon-gamma: a key contributor to hyperoxia-induced lung injury in mice. Am J Physiol Lung Cell Mol Physiol 287: L1042–L1047
Suzumura A, Sawada M, Takayanagi T 1998 Production of interleukin-12 and expression of its receptors by murine microglia. Brain Res 787: 139–142
Bright JJ, Musuro BF, Du C, Sriram S 1998 Expression of IL-12 in CNS and lymphoid organs of mice with experimental allergic encephalitis. J Neuroimmunol 82: 22–30
Olson JK, Miller SD 2004 Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173: 3916–3924
Oyama J, Blais C Jr, Liu X, Pu M, Kobzik L, Kelly RA, Bourcier T 2004 Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation 109: 784–789
Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST, Brennan PJ, Bloom BR, Godowski PJ, Modlin RL 1999 Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285: 732–736
Dohlen G, Carlsen H, Blomhoff R, Thaulow E, Saugstad OD 2005 Reoxygenation of hypoxic mice with 100% oxygen induces brain nuclear factor-kappa B. Pediatr Res 58: 941–945
Ohashi K, Burkart V, Flohe S, Kolb H 2000 Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 164: 558–561
Termeer CC, Hennies J, Voith U, Ahrens T, Weiss JM, Prehm P, Simon JC 2000 Oligosaccharides of hyaluronan are potent activators of dendritic cells. J Immunol 165: 1863–1870
Acknowledgements
The authors thank the assistance of Ingela Mattisson-Sandstrom, Ulla Gahnestam, and Ann-Cathrin Berg for assistance during the experimental sheep study and Irene Larsson assistance in the analysis of ovine gene expression.
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This work was supported by The Swedish Medical Research Council (grants 14940, 4732), Lund University Hospital and Lund Medical Faculty grants, the Segerfalk Foundation, the Craaford foundation, and the Rikshospitalet-Radiumhospitalet Health trust.
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Markus, T., Hansson, S., Amer-Wåhlin, I. et al. Cerebral Inflammatory Response After Fetal Asphyxia and Hyperoxic Resuscitation in Newborn Sheep. Pediatr Res 62, 71–77 (2007). https://doi.org/10.1203/PDR.0b013e31811ead6e
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DOI: https://doi.org/10.1203/PDR.0b013e31811ead6e
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